Patent FR-2866884-A1 (FR)
Title: New C-alkyl-piperidine-1-carboxylate derivatives and analogs, are fatty acid amidohydrolase inhibitors useful for treating e.g. pain, cancer or neurodegenerative, cardiovascular, inflammatory or allergic disease
Inventor: ABOUABDELLAH AHMED
IPC: C07D211/60
Filed: 2004-02-26
Abstract: Carbamoylalkyl C-((hetero)aryl or (hetero)aryl-substituted alkyl)-azetidine, pyrrolidine, piperidine or homopiperidine 1-carboxylates (I) are new. Also new are carbamate-ester derivative intermediates (IV). Azetidine, pyrrolidine, piperidine or homopiperidine derivatives of formula (I) and their acid addition salts, hydrates and solvates are new. Q x(CH 2) n ; Q y(CH 2) m; A : direct bond; or one or more of X, Y and/or Z; X : CH 2 (optionally substituted (os) by 1 or 2 of alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl); Y : 2C alkenylene (os by 1 or 2 of alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl) or 2C alkynylene; Z : 3-7C cycloalkylidene or 3-7C cycloalkylene; R 1R 5 (os by one or more groups R 6 and/or R 7); R 2H, F, OH, alkoxy or NR 8R 9; R 3H or alkyl; R 4H, alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl; R 5phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl, quinolinyl, tetrahydro-quinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl or isothiazolopyridinyl; R 6halo, CN, NO 2, alkyl, alkoxy, OH, alkylthio, fluoroalkyl, fluoroalkoxy, fluoroalkylthio, NR 8R 9, NR 8COR 9, NR 8COOR 9, NR 8SO 2R 9, COR 8, COOR 8, CONR 8R 9, SO 2R 8, SO 2NR 8R 9 or 1-3C alkylenedioxy; R 7phenyl, phenoxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl (all os by one or more groups R 6); R 8, R 9H or alkyl; or NR 7R 8azetidino, pyrrolidino, piperidino, morpholino, thiomorpholino, azepino or piperazino (all os by alkyl or benzyl); m,n : 1-3; provided that m + n = 2-5; and p : 1-7. alkyl moieties have 1-6C and cycloalkylene moieties 3-7C unless specified otherwise. Independent claims are also included for: (A) the preparation of (I); and (B) new carbamate-ester derivative intermediates of formula (IV). R : Me or Et. [Image] [Image] ACTIVITY : Analgesic; Antimigraine; Auditory; Antiemetic; Anorectic; Immunomodulator; Neuroleptic; Relaxant; Tranquilizer; Antidepressant; Neuroprotective; Antiparkinsonian; Nootropic; Anticonvulsant; Cerebroprotective; Nephrotropic; Cardiant; Hypotensive; Antiarrythmic; Antiarteriosclerotic; Vasotropic; Cytostatic; Immunosuppressive; Antipsoriatic; Dermatological; Antianemic; Antiallergic; Antiparasitic; Virucide; Antibacterial; Anti-HIV; Antiinflammatory; Antiarthritic; Antirheumatic; Osteopathic; Antigout; Ophthalmological; Antitussive; Antiasthmatic; Antiulcer; Antidiarrheic; Uropathic. In phenylbenzoquinone-induced writhing tests for analgesic activity in mice, the most active compounds (I) (not specified) inhibited writhing by 35-70% at doses of 1-30 mg/kg p.o. or i.p. MECHANISM OF ACTION : Fatty acid amidohydrolase (FAAH) inhibitor. 2-(Methylamino)-2-oxoethyl 4-(4'-methoxybiphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate (Ia) had IC 50 95 nM for inhibition of FAAH.